Schistosomiasis remains a major parasitic infection of man and animals in numerous developing countries. Schistosoma japonicum is found in southeast Asia and China and is a zoonotic disease, infecting water buffalo, cattle and other livestock as well as man. A mathematical model of schistosomiasis reveals that water buffalo account for approximately 80% of transmission in China and predicts that vaccines with 40-45% efficacy will significantly reduce transmission of schistosomiasis in China. We performed two vaccine efficacy trials in water buffalo using SjCTPI-Hsp70 and SjC23-Hsp70 plasmid DNA vaccines in combination with an IL-12 expressing plasmid. The results show that the SjC23-Hsp70 and SjCTPI-Hsp70 vaccines each induced efficacy of 50% or greater in reductions in adult worm burden, liver eggs and importantly in fecal miracidial hatching rates compared to pVAX plasmid DNA vaccinated buffalo. The goal of this revised application is to determine which aspects of the formulation are required for this high level of vaccine efficacy and then to modify vaccine formulation and delivery to enhance the efficacy of each of these vaccines. Thus vaccine trials will be performed to confirm that the inclusion of Hsp70 in the plasmid DNA constructs enhances vaccine efficacy and determine if co-administration of an IL-12 expressing plasmid is also required. We will next determine if vaccine efficacy can be enhanced by administration of a protein antigen boost instead of a plasmid DNA boost and we will compare boosting with soluble recombinant SJC23 and SjCTPI antigens as well as these antigens conjugated to micro-beads to enhance antigen presenting cell activation. We will then determine if co-administration of the optimal form of both vaccines induces greater efficacy in water buffalo than buffalo vaccinated with either single vaccine. We believe the proposed studies will give rise to one or more prophylactic vaccines with levels of efficacy greater than the 50% level we already have, that will be used in China and other regions of southeast Asia to reduce transmission of schistosomiasis. Aim 1. Determine if SJC23 and SjCTPI vaccine efficacy in water buffalo requires the use of IL-12 or Hsp70. Aim 2. Determine if a protein antigen boost, either soluble or as micro-bead conjugates increase efficacy of SJC23 or SjCTPI vaccines in water buffalo? Aim 3. Determine if vaccination with a combination of the optimized SJC23 and SjCTPI vaccines induce greater efficacy in water buffalo than when either vaccine is administered singly?